Malaria is one of the world's most devastating diseases and is responsible for between 1-2 million deaths each year. Malaria is transmitted by the bite of a female mosquito infected with the malaria parasite. Female mosquitoes of the species Anopheles gambiae are feed almost exclusively on humans and use odors present in human sweat and skin to locate their targets and discriminate humans from other animals. The overall goal of this proposal is to understand the molecular events that control the host seeking behavior of the mosquito in order to develop new methods to reduce the transmission of malaria. Odor detection by an insect requires the interaction of a number of protein components. Among these are the Odorant Receptors and the Odorant Binding Proteins (OBPs). The OBPs transport the odor molecule from the surface of the olfactory hairs (sensilla) to the receptors and accumulating evidence suggests that OBPs may directly mediate the activity of some odorant receptors. In female A. gambiae mosquitoes, the expression patterns of a number of OBPs correlate with changes in the host-seeking behavior. Therefore, it is hypothesized that these proteins may be associated with mediating olfactory responses to human odors. This proposal will investigate how these OBPs interact with human-specific odors by examining the structure and ligand-binding properties of these proteins. This proposal will use Nuclear Magnetic Resonance (NMR) Spectroscopy to identify which odors interact with specific OBP. Subsequently we will determine the three-dimensional structure of these complexes, and correlate differences in binding affinities for particular odorants with specific interactions that occur between the OBP and the odorant. We will seek to answer the questions;do AgOBPs act as specific modulators of olfactory signaling in response to human odors? Do ligands induce specific conformational changes in the AgOBPs that could indicate a direct role in activation of odorant receptors? Once the nature of the interactions between specific AgOBPs and odor molecules are defined, this information will be used to guide the design of new reagents targeted at OBPs, with the aim of disrupting normal Anopheline mosquito behavior and so reducing the transmission of malaria.